I.kappa.B comprises a family of regulatory molecules for the NF.kappa.B transcription factor family. The NF.kappa.B factors are important effectors of function of a number of pro-inflammatory factors, such as cytokines (e.g., IL-1, IL-6, IL-8, and TNF) and the redox system (reduction/oxidation). The regulation of the activation of NF.kappa.B is an important target for therapeutic intervention of inflammatory diseases.
The activation of NF.kappa.B by diverse pro-inflammatory factors involves a cascade of molecules from the cell surface receptors of the cytokines to the cytosolic signaling molecules. The final and common step of NF.kappa.B activation is controlled by the I.kappa.B family of molecules. The I.kappa.B family consists of I.kappa.B.alpha., I.kappa.B.beta., I.kappa.B.gamma., and other I.kappa.B related proteins, such as Bc1-3, which inhibit the nuclear translocation and DNA binding of NF.kappa.B through complex formation with the NF.kappa.B family of factors in both the cytoplasm and the nucleus. The final activation of NF.kappa.B is achieved through the phosphorylation and subsequent degradation of the complexed I.kappa.B protein, which releases the NF.kappa.B factor to be translocated into the nucleus and bound to NF.kappa.B-specific DNA sequences in the promoters of NF.kappa.KB target genes, functioning as a transcriptional activator.
The diverse initial activation factors of NF.kappa.B converge into the final step of activation of I.kappa.B kinase (IKK), which specifically phosphorylates the inhibitory I.kappa.B factor and results in subsequent degradation of I.kappa.B factors. IKK proteins are therefore critical targets for anti-inflammatory drug development. Thus, there is a need in the art for identifying new components of this important regulatory system.